Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective Xpg mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging

T Cell Primary Effusion Lymphoma in an HIV-Negative Man with Liver Cirrhosis.

BACKGROUND Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma (NHL) that is responsible for 1% of all lymphomas not related to human immunodeficiency virus (HIV). PEL is characterized by human herpesvirus-8 (HHV-8) positivity in the absence of overt tumor burden that does not exhibit typical B cell or T cell immunophenotype characteristics. The exact mechanism of development is unknown, but it is hypothesized to develop from post-germinal B cell origin. Although it is most common in HIV patients, other immunocompromising comorbidities can be seen in conjunction with PEL, including liver cirrhosis. CASE REPORT We present the case of a 73-year-old HIV-seronegative man with alcohol-induced liver cirrhosis who was found to have T cell PEL of the pleural space diagnosed by thoracentesis. CONCLUSIONS Little is known regarding oncogenesis of T cell PEL, and few studies exist regarding appropriate treatment regimens for PEL as a whole, prompting need for further investigation and discussion to improve survival rates. Even in the absence of active HIV infection, PEL should be considered as a potential cause of pleural effusion in cirrhotic patients in order to prompt earlier treatment for the best chance of survival

High torsion stiffness leafspring flexure element using distributed warping constraints

Leafsprings are commonly used in flexure mechanisms to enable repeatable motion and provide support stiffness. In various applications, the torsional stiffness needs to be increased. This paper presents the concept of using warping constraints distributed along the leafspring to increase the torsional stiffness relative to the stiffness in other directions. A beam-based model of nonuniform torsion is used to estimate the relationship between the geometrical design parameters and the expected increase in torsional stiffness. The model predicts that an order of magnitude increase in stiffness is feasible. Compared to other solutions, the distributed warping constraints have a less obtrusive shape that offer more design freedom

Active vibration isolation with integrated virtual balance mass for a motion stage

Many precision machines, such as wafer scanners, have an internal motion stage. These stages generate reaction forces that act directly on the machine frame. A common method to minimize the effect of these reaction forces is a balance mass. To eliminate the need for this balance mass, it is proposed to use an active vibration isolation system as a virtual balance mass. Such can be achieved by constructing a force that is based on the reference of the motion stage that cancels its correlated reaction force. This appends the primary objective of an active vibration isolation system, which is to reduce the sensitivity to direct and indirect disturbances. A self-tuning algorithm is implemented to deal with parameter uncertainty and variation. The performance of the proposed method is experimentally validated on a 6-DoF active vibration isolation system, which is appended with a flexure based, straight guided motion stage. A 300 Hz frame mode is introduced of which the displacement can be measured to assess the performance of the method. The proposed method improved the tracking accuracy of the motion stage by a factor of 3.8 and reduced the settling time of the frame mode by a factor of 91, compared to the system without a virtual balance mass

Design of a large deflection compliant mechanism with active material for vibration suppression

The control bandwidth of a flexure mechanism is typically limited by parasitic resonance frequencies with low structural damping. Such resonances can be suppressed by including active material in the mechanism, which is used to dissipate energy at specified frequencies. The active material is typically placed in areas with high strain, in order to obtain the highest possible coupling and therefore dissipation. However, due to the low ultimate strain of some common active materials, the included active material will limit the deflection of the mechanism. In this work we introduce a design method that improves the closed-loop performance of a low pivot shift cross hinge mechanism by including active material in the leaf springs, without sacrificing the achievable deflection of the mechanism. The coupling between the active material and a selected undesired parasitic frequency is maximised by placing the material in locations with high modal strain. At the same time, the piezoelectric patches are only included in regions where the strain due to the nominal deflection is limited, such that the maximum deflection of ± 15 degrees is maintained. Using the patches as sensors and actuators, positive position feedback control is applied. Using simulations, it is shown that a selected resonance peak can be decreased by 16.3 dB for the considered mechanism, enabling 88% higher bandwidth

CD4+ cell counts and HIV-RNA levels do not predict outcomes of community-acquired pneumonia in hospitalized HIV-infected patients

Outcomes of community-acquired pneumonia (CAP) in relation to CD4+ cell counts have not been established. We examined the correlation of CD4+ cell count and HIV-RNA level with the clinical outcomes of CAP in hospitalized HIV-infected patients. METHODS: This was a retrospective study of 127 adult hospitalized patients with HIV infection enrolled with the CAP Organization (CAPO), examining the time to clinical stability (TCS), length of hospital stay (LOS), and all-cause mortality. RESULTS: Mortality data were available for 117 HIV-infected patients with CAP. Death within 28 days was reported in 28 patients. The risk of mortality at 28 days was not significant when adjusted for CD4+ cell count (p=0.123), HIV-RNA <400-1000 copies/ml (p=0.093), HIV-RNA ≥ 1000-10,000 copies/ml (p=0.543), and HIV-RNA ≥ 10,000-100,000 copies/ml (p=0.383). The propensity-adjusted Cox proportional hazards regression models did not show any statistically significant differences in LOS or TCS for CD4+ cell counts (p=0.590 and p=0.420, respectively) or HIV-RNA levels (p=0.470 and p=0.080, respectively). Multivariable Cox proportional hazards models did not reveal any statistically significant relationships between CD4+ cell counts or HIV-RNA levels with LOS or TCS. CONCLUSIONS: Our study shows that clinical outcomes of HIV-infected patients with CAP are not predicted by CD4+ cell counts or HIV-RNA levels after adjusting for confounders. The management of CAP in patients with HIV infection should not be based on CD4+ cell counts or HIV-RNA levels of the HIV infection

Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging

Bacteremic pneumococcal pneumonia : clinical outcomes and preliminary results of inflammatory response

Purpose: Further examination of clinical outcomes and inflammatory response of bacteremic pneumococcal community-acquired pneumonia (CAP) is of great interest to enhance the care of patients with pneumococcal CAP. Methods: This is a secondary analysis of the Community Acquired Pneumonia Organization (CAPO) to compare the time to clinical stability (TCS), length of hospital stay (LOS), and in-hospital mortality of hospitalized pneumococcal CAP patients with and without bacteremia. To measure the effect of bacteremia in pneumococcal CAP patients on outcomes, we modeled all-cause in-hospital mortality using a Poisson regression model, and TCS and LOS using Cox proportional hazards models. Adjusted multivariate regression models were also used to predict the probability of occurrence of each of the study outcomes. To investigate the inflammatory response, we measured the plasma levels of pro- and anti-inflammatory cytokines [tumor necrosis factor (TNF)-\u3b1, interleukin (IL)-1r\u3b1, IL-6, IL-8, IL-10], inflammatory biomarkers [C-reactive protein (CRP), pro-calcitonin (PCT), and B-type natriuretic peptide (BNP)], and peripheral blood neutrophil responses in 10 patients, 4 bacteremic and 6 non-bacteremic pneumococcal CAP, upon admission and every other day during the first 6 days of hospitalization. Functional data were presented as median and standard error of the median (SEM); due to small number of samples no statistical comparisons were performed between groups. Results: From 833 pneumococcal CAP patients, 394 patients (47 %) were bacteremic. Bacteremic pneumococcal CAP were less likely to reach TCS with an adjusted hazard ratio (AHR) of 0.82 (95 % CI 0.69\u20130.97; p = 0.02) and had higher in-hospital mortality with an AHR of 1.63 (95 % CI 1.06\u20132.50, p = 0.026). Bacteremic pneumococcal CAP patients had a longer LOS than non-bacteremic pneumococcal CAP (p < 0.003). Higher plasma levels of CRP, PCT, and BNP were found in bacteremic than in non-bacteremic patients. The bacteremic group had consistently higher plasma levels of both pro- and anti-inflammatory cytokines. The blood neutrophil functional responses were similar in both groups of patients. Conclusions: Bacteremic pneumococcal CAP patients were significantly associated with higher in-hospital mortality, lower TCS, and longer LOS. HIV-infected patients showed a greater mortality which was not statistically significant. Bacteremic pneumococcal CAP patients had higher levels of biomarkers and systemic cytokines

Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging. It is unclear how the loss of XPG protein causes the neurodevelopmental disorder Cockayne syndrome with death in early childhood. Trego et al. show that XPG partners with BRCA1 and BRCA2 to maintain genomic stability through homologous recombination, and its loss causes DNA breaks, chromosome aberrations, and replication fork stalling